The first examples of di- and cis triaryl-3a,4,5,6- tetrahydroimidazo[1,5-b]isoxazoles and their ring-opening reactions

Article abstract of DOI:10.1016/S0040-4039(00)00864-9

The Δ³-imidazoline 3-oxides 1 undergo diastereoselective cycloaddition with dimethyl acetylenedicarboxylate 2 to give 3a,4,5,6- tetrahydroimidazo[1,5-b]isoxazoles 3. Thermal and base induced ring-opening reactions of compounds 3 were demonstrat

Full text of DOI:10.1016/S0040-4039(00)00864-9

Tetrahedron Letters 41 (2000) 5407±5409
The ®rst examples of di- and cis
triaryl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles
and their ring-opening reactions
Necdet Coskun,a,* Fatma Tirli Tat,a Ozden Ozel Guven,b
Dincer Ulkuc and Cengiz Arõcõc
aUludagÆ University, Department of Chemistry, 16059 Bursa, Turkey
bZonguldak Karaelmas University, Department of Chemistry, 67100 Zonguldak, Turkey
cDepartment of Engineering Physics, Hacettepe University, Beytepe, 06532 Ankara, Turkey
Received 13 March 2000; accepted 23 May 2000
Abstract
The Á3-imidazoline 3-oxides 1 undergo diastereoselective cycloaddition with dimethyl acetylenedi-
carboxylate 2 to give 3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles 3. Thermal and base induced ring-opening
reactions of compounds 3 were demonstrated. # 2000 Elsevier Science Ltd. All rights reserved.
The inter- and intramolecular 1,3-dipolar cycloadditions of nitrones with di€erent dipolaro-
philes provide valuable routes leading to many heterocyclic compounds. The cycloaddition of
nitrones with a variety of alkynes is used in the synthesis of isoxazolines.1 3 The intramolecular
1,3-dipolar cycloaddition of acetylenic nitrones leading to bicyclic nitrogen heterocycles has been
investigated.4 Intermolecular 1,3-dipolar cycloaddition of acyclic5 8 and cyclic nitrones9 12 with
DMAD have been reported. Dihydroazet-1-oxide,9 dihydro-b-carboline N-oxide,10 and 3,4-
dihydro-2H-pyrrole 1-oxide derivatives11,12 are the few known heterocyclic nitrones which have
been used in 1,3-dipolar cycloaddition reactions with DMAD. The synthesis of the ®rst examples
of the 4H-imidazo[4,5-c]isoxazole ring system was recently reported.13
As part of a continuing study into new tetrahydroimidazole containing ring systems14,15 possessing
antibacterial and anticancer activity we have used imidazoline N-oxides as cyclic nitrones and
DMAD as a dipolarophile to prepare the corresponding tetrahydroimidazoisoxazole bicyclic
system. We report herein a diastereoselective synthesis of a new class of 3a,4,5,6-tetrahydro-
imidazo[1,5-b]isoxazole by cycloaddition of Á3-imidazoline 3-oxides with dimethyl acetyl-
enedicarboxylate as well as their thermal and base induced ring opening reactions (Scheme 1).
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00864-9

5408
Scheme 1.
The reaction of the nitrones 1a±e with dimethyl acetylenedicarboxylate in benzene at re¯ux
gave the corresponding imidazoisoxazolines 3 in almost quantitative yields.17 Nitrones 1d,e reacted
with dimethyl acetylenedicarboxylate with high diastereoselectivity. A tentative cis con®gurational
1
assignment11,12 for compounds 3d,e was made on the basis of H NMR spectroscopic data and
NOESY experiments. We have observed the same diastereoselectivity as has been observed in the
reaction of imidazoline oxides 1 with aryl isocyanates and styrene.14 16
Thermal treatment of compounds 3a±e in the condensed phase under vacuum led to the forma-
tion of the imidazoles. This was in contrast with the behaviour of the imidazoline 3-oxides'
adducts formed from isocyanates and styrene where thermal treatment led to retro 1,3-dipolar
cycloaddition.
In the case of cis 3a,6-diaryltetrahydroimidazo[1,5-b][1,2,4]oxadiazol-2(1H)-ones we have
found that secondary amines open the ring producing imidazole while tertiary amines led to retro
1,3-dipolar cycloaddition giving the starting cyclic nitrone.18 The adducts obtained from the same
imidazoline oxides and styrene did not undergo reaction with secondary and tertiary amines. This
reaction would have been useful in distinguishing the diastereomers obtained from the reaction of
Figure 1. 3D Perspective view of the crystal structure of 3e

5409
imidazoline 3-oxides and isocyanates, the cis con®guration was assigned tentatively on the basis
of NOE experiments and the second diastereomer was not available by cycloaddition reaction.
The adducts 3 were subjected to the same amine test and showed surprisingly similar behaviour to
the imidazooxadiazolones. Compounds 3a±e were converted to imidazoles 4a±e and dimethyl
oxaloacetate in re¯uxing acetonitrile in the presence of an excess of piperidine. Compounds 3d±e
were converted to the corresponding imidazoles in the presence of piperidine but remain
unchanged in the presence of triethylamine under the same reaction conditions. The easy ring-
opening of adducts 3 led us to suspect an abnormality in their formation. Such an abnormal
adduct would be formed if imidazoline 3-oxides react via their rearranged oxaziridinoimidazole16
form to give dimethyl 5,6,7,7a-tetrahydroimidazo[5,1-b][1,3]oxazole-2,3-dicarboxylates. The IR
1
and H NMR spectra were consistent with both structures therefore we needed to elucidate this
structure by an X-ray di€raction method. The adduct is proved unequivocally to be the cis-isomer
by X-ray crystallographic analysis. A 3D perspective view of the crystal structure of 3e is shown
in the Fig. 1. Thus the con®guration of adducts 3d,e has to be cis for the double cis elimination
with secondary amines.
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J=11), 3.64 (3H, s), 3.87 (3H, s), 4.19 (1H, d, J=11), 4.65 (1H, d, J=11), 5.05 (1H, d, J=11), 6.71 (2H, d, J=8),
7.08 (2H, d, J=8), 7.28±7.39 (3H, m), 7.60 (2H, d, J=8); MS m/z 394 (M+).
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